UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factor 2 (FGF2), also known as basic fibroblast growth factor (bFGF), belongs to the FGF family, which consists of at least 9 closely related members. FGF2 is a potent mitogen for fibroblasts derived from normal prostate and, to a lesser extent, for prostatic epithelial cells. Its role in the physiology of the normal prostate seems to be limited to stromal cells, whereas in prostate cancer FGF2 may also have an autocrine/paracrine effect on epithelial cells. In order to better understand the effects of FGF2 on the prostatic epithelium, especially its role in the progression of prostate cancer by establishing an autocrine-stimulation loop, we transfected FGF2 cDNA into a human prostatic epithelial cell line, PNT1A, immortalized with SV40 large-T antigen. This cell line is non-tumorigenic and expresses a high-affinity FGF2 receptor, FGFR1/flg. We characterized 3 independent FGF2-transfected clones and found that the establishment of an FGF2 autocrine loop on these cells led to (i) serum-independent growth, (ii) increased proliferation and (iii) anchorage-independent growth. Such results argue in favor of the possible action of FGF2 on progression of prostate cancer via an FGF2 autocrine loop on epithelial cells.
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PMID:Constitutive expression of FGF2/bFGF in non-tumorigenic human prostatic epithelial cells results in the acquisition of a partial neoplastic phenotype. 924 2

Cellular interactions between stroma and epithelium are important in the growth and proliferation of prostate cancer. Peptide growth factors may facilitate the progression of prostate cancer as autocrine and/or paracrine factors. Keratinocyte Growth Factor (KGF or FGF7) has a differentiative and proliferative effect on the epithelium of the developing rat prostate. We investigated if KGF may act as a paracrine agent in human prostate cancer and examined the expression of KGF and Fibroblast Growth Factor Receptors (FGFRs) (IIIb and IIIc isoforms of the FGFR1 and FGFR2 genes). Sixty-five percent (11 out of 17 informative cases) of prostate cancers (CaP) expressed KGF mRNA by RT-PCR, while KGF expression was not detected in benign prostatic hyperplasia (BPH) (n = 6). Upregulation of KGF expression was related to hormone insensitive tumours (P<0.05). Tumour grade and stage were not associated with KGF expression. The source of KGF expression was further characterised using an in vitro primary culture model, showing its restriction to the prostatic stroma. The FGFR1IIIb isoform was expressed in all cases of prostate cancer (n = 17), and FGFR1IIIc mRNA was not detected. In the BPH group, FGFR1IIIb transcripts were detected in four out of six cases. FGFR2IIIb expression was detected in five of six cases of BPH and twelve out of seventeen (71%) cases of prostate cancer. In CaP, though not reaching statistical significance, the persistence of FGFR2IIIb expression appeared to be associated with hormone insensitive tumours (P=0.052). FGFR2IIIc expression was present in eleven of seventeen tumours but was absent in all six cases of BPH. Functional assessment of recombinant KGF in a proliferation assay demonstrated a mitogenic effect of up to 100% on cultured prostatic epithelial cells.
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PMID:Keratinocyte growth factor expression in hormone insensitive prostate cancer. 928 67

In prostate cancer, a distinct series of alterations in the fibroblast growthfactor (FGF) family occurs during the progression from a hormone-dependent to independent state that disrupts communication between stroma and epithelium and results in autonomy of cancer cells. Changes include (i) loss of FGFR2IIIb, whichbinds stromal-derived FGF-7, which promotes growth, growth limitation and differentiation and (ii) activation of FGFR1, the expression of which is normally limited to stroma, along with activation of FGFs that act on FGFR1 in an autocrine manner. Transfection of the FGFR2IIIb isoform into hormone-independent prostate cancer cells not only causes growth inhibition, but also induces differentiation. However, introduction of FGFR1 by transfection in hormone-dependent prostate cancer cells accelerates their progression to malignancy. These results suggest distinct targets for therapy aimed at both inhibition of the malignant phenotype and restoration of homeostasis.
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PMID:Hormone Refractory Prostate Cancer and Fibroblast Growth Factor Receptor. 1109 37

The abnormal appearance and age-dependent loss of resident fibroblast growth factor receptor-2 (FGFR2) and gain of activity of FGFR1 in epithelial cells is a hallmark of the slow progression to malignancy in some models of prostate cancer. Pericellular matrix heparan sulfate (HS) is an integral subunit of the FGFR tyrosine kinase complex that restricts activity in absence of FGF, facilitates binding of an activating FGF, and confers specificity for FGF isoforms. In this report, we isolated and purified HS proteoglycan (HSPG) from premalignant prostate tumor epithelial cells based on the ability of the HS chains to form a binary complex with immunoglobulin module II of the ectopic and progression-promoting FGFR1 that was competent to bind FGF. The FGFR1 affinity-purified product exhibited a specific activity of over 600 times that of crude cellular HSPG enriched from cell lysates by ion exchange chromatography. The purified preparation exhibited a single NH(2)-terminal sequence with 11 of 13 residues identical to syndecan-1. The activity of purified recombinant glutathione S-transferase-tagged syndecan-1 expressed in premalignant epithelial cells confirmed that syndecan-1 bears HS chains that exhibit the rare motif that forms the FGF-binding complex with ectopic FGFR1. These results are the first to identify by affinity purification a specific HSPG core protein, the HS chains of which act as an integral subunit of the FGFR complex. The results suggest that syndecan-1 provides HS chains in premalignant epithelial cells to both the FGFR2- and FGFR1-signaling complexes that are integral to their dual roles in progression to malignancy.
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PMID:A rare premalignant prostate tumor epithelial cell syndecan-1 forms a fibroblast growth factor-binding complex with progression-promoting ectopic fibroblast growth factor receptor 1. 1143 73

In recent decades, radiation research has concentrated primarily on the cancer cell compartment. Much less is known about the effect of ionizing radiation on the endothelial cell compartment and the complex interaction between tumor cells and their microenvironment. Here we report that ionizing radiation is a potent antiangiogenic agent that inhibits endothelial cell survival, proliferation, tube formation and invasion. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were able to reduce the radiosensitivity of endothelial cells. Yet, it is also found that radiation induces angiogenic factor production by tumor cells that can be abrogated by the addition of antiangiogenic agents. Receptor tyrosine kinase inhibitors of Flk-1/KDR/VEGFR2, FGFR1 and PDGFR beta, SU5416, and SU6668 enhanced the antiangiogenic effects of direct radiation of the endothelial cells. In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668. Furthermore, ionizing radiation up-regulated VEGF and basic fibroblast growth factor in PC3 cells and VEGFR2 in endothelial cells. Together these findings suggest a radiation-inducible protective role for tumor cells in the support of their associated vasculature that may be down-regulated by coadministration of angiogenesis inhibitors. These results rationalize concurrent administration of angiogenesis inhibitors and radiotherapy in cancer treatment.
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PMID:SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. 1283 71

Changes in the fibroblast growth factor receptor (FGFR) axis are often associated with prostate cancer (CaP) progression. We have used chemically induced dimerization (CID) to elucidate the individual contributions of FGFR1 and FGFR2 to tumor etiology. Novel CaP cell lines stably expressing CID/AP20187-inducible FGFR1 (iFGFR1) and iFGFR2 were made using the tumorigenic transgenic adenocarcinoma of the murine prostate (TRAMP)-derived clone, TRAMP-C2N (C2N), to generate C2N.iFGFR1 or C2N.iFGFR2 cells. To test the effects of iFGFR activation on tumor growth, mice bearing s.c. C2N.iFGFR1- or C2N.iFGFR2-derived tumors were treated biweekly with CID. Activation of iFGFR1 led to rapid tumor growth as a result of increased proliferation. In contrast, expression of iFGFR2 inhibited tumor growth. Furthermore, we have ascertained that FGFR1 activation appears to be most important during the early stages of tumor development, but once established, tumors become rapidly CID independent. In these C2N-based lines, quantitative signaling differences were seen between the two receptors, with iFGFR1 leading to more robust extracellular signal-regulated kinase activation. Additionally, activation of iFGFR1, but not iFGFR2, led to strong up-regulation of osteopontin, a secreted glycoprotein involved in integrin activation and associated with CaP progression and metastasis. These studies support the hypothesis that observed changes in the FGFR axis in mammals during CaP progression are causally important.
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PMID:Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation. 1455 9

Accurate determination of the contributions of oncogenes toward tumor progression requires their regulation. Herein, we created transgenic mice with prostate-specific expression of ligand-inducible FGFR1 or FGFR2, based on lipid-permeable dimerizing molecules, called chemical inducers of dimerization. Despite extensive homology and equivalent expression by both chimeric receptors in the ventral prostate gland, only FGFR1 triggers detectable nuclear translocation of Erk and progression to prostatic intraepithelial neoplasia (PIN). Induction of PIN grade I-II, indicated by multiple layers of atypical cells, is seen consistently by 12 weeks of chemical inducers of dimerization treatment. By 6 months, more extensive nuclear atypia, thickened "reactive" stroma, and basement membrane herniation occurs, corresponding to PIN IV. By timed removal of FGFR1 signaling, we show that induced hyperplasia is reversible until extensive intraductal vascularization occurs, but continued progression requires prolonged FGFR1 signaling. Additionally, by highlighting differences between the two receptors and creating the foundation for controlling FGFR1 signaling during prostate cancer progression, a model of early stage prostate cancer is established for developing targeted intervention directed toward the FGFR signaling axis.
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PMID:Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. 1467 83

Disruption of the regulatory communication from the stroma to the epithelium mediated by the FGF7/10-FGFR2 signaling axis in the prostate and expression of ectopic FGFR1 in prostatic epithelial cells often correlate with prostate cancer progression both in human and in experimental animals. Ectopic expression of constitutively active FGFR1 mutant (caFGFR1) at low levels in prostate epithelial cells induces low- to intermediate-grade prostatic intraepithelial neoplasia (PIN) within 6-8 months and high-grade PIN in 20-25 months. Depression of the FGFR2 signaling in the prostate also disturbs homeostasis in the prostate and induces prostate hyperplasia. To study whether PIN lesions induced by the caFGFR1 were expression-level dependent, and whether expression of the caFGFR1 and depression of the FGFR2 signaling in the prostate synergistically disturbed prostate homeostasis, we generated two new strains of ARR2PBi-caFGFR1 transgenic mice, which highly expressed caFGFR1 in prostatic epithelial cells. The mice were crossed with KDNR mice to generate ARR2PBi-caFGFR1/KDNR bigenic mice. The ARR2PBi-caFGFR1 mice developed high-grade PIN within 8 months, which was significantly faster than the mice expressing caFGFR1 at low levels. In addition, depression of the FGFR2 signaling clearly promoted perturbation of cellular homeostasis induced by the caFGFR1. The results demonstrated that the PIN development in caFGFR1 transgenic mice was caFGFR1 dosage-dependent, and indicated that the ectopic FGFR1 and the resident FGFR2 in epithelial cells had opposite impacts on intercompartmental homeostasis in the prostate. The bigenic mice provide a model with cooperative aberrations in the fibroblast growth factor signaling axis for evaluation of tumor-initiating events in prostate tumorigenesis.
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PMID:Cooperation between ectopic FGFR1 and depression of FGFR2 in induction of prostatic intraepithelial neoplasia in the mouse prostate. 1469 95

Understanding processes regulating prostate cancer cell survival is critical to management of advanced disease. We used prostate cancer cell transfectants genetically modified to be deficient in either endogenous fibroblast growth factor (FGF-1) or endogenous FGF-2 to examine FGF maintenance of transfectant survival and proliferation and FGF-2-regulated expression of transfectant growth arrest DNA damage (GADD) and growth arrest sequences (GAS) family genes (known modulators of cell cycle progression and survival) and the AS3 gene (an androgen-modulated effector of prostate cell proliferation). When propagated in the absence of exogenous FGFs, FGF-2-deficient transfectants undergo exponential death, whereas FGF-1-deficient transfectants proliferate. Exogenous FGF-1, FGF-2, FGF-7, or FGF-8 promote survival and proliferation of FGF-2-deficient transfectants and enhance FGF-1-deficient transfectant proliferation. Transfectants express FGF receptor FGFR1, FGFR2(IIIb), FGFR2(IIIc), and FGFR3 transcripts, findings consistent with the effects of exogenous FGFs. FGF-2-deficient transfectants express high levels of AS3, GADD45alpha, GADD45gamma, GAS8, and GAS11 transcripts and moderate levels of GADD153, GAS2, GAS3, and GAS6 transcripts and lack demonstrable GAS1 or GAS5 transcripts. FGF withdrawal-mediated death of FGF-2-deficient transfectants did not significantly affect cell AS3, GADD153, GADD45gamma, GAS2, GAS3, GAS7, GAS8, or GAS11 transcript content, whereas GADD45alpha and GAS6 transcript content was elevated. These studies establish that endogenous FGF-2 dominantly regulates prostate cancer cell survival and proliferation and that exogenous FGFs may assume this function in the absence of endogenous FGF-2. Additionally, we provide the first evidence that FGFs regulate prostate GADD45alpha and GAS6 transcript content. The latter observations suggest that GADD45alpha and GAS6 proteins may be effectors of processes that regulate prostate cancer cell survival. Additional studies are required to examine this possibility in detail.
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PMID:Exogenous fibroblast growth factors maintain viability, promote proliferation, and suppress GADD45alpha and GAS6 transcript content of prostate cancer cells genetically modified to lack endogenous FGF-2. 1556 81

Overexpression of fibroblast growth factors (FGFs) has been implicated in prostate carcinogenesis. FGFs function via their high-affinity interactions with receptor tyrosine kinases, FGFR1-4. Expression of FGFR1 and FGFR2 in prostate cancer (CaP) was not found to be associated with clinical parameters. In this report, we further investigated for abnormal FGFR expression in prostate cancer and explore their significance as a potential target for therapy. The expression levels of FGFR3 and FGFR4 in CaP were examined and corroborated to clinical parameters. FGFR3 immunoreactivity in benign prostatic hyperplasia (BPH) and CaP (n=26 and 57, respectively) had similar intensity and pattern. Overall, FGFR4 expression was significantly upregulated in CaP when compared to BPH. A significant positive correlation between FGFR4 expression and Gleason score was noted: Gleason score 7-10 tumours compared to BPH (P<0.0001, Fisher's exact test), Gleason score 4-6 tumours compared to BPH (P<0.0004), and Gleason 7-10 compared to Gleason 4-6 tumours (P<0.005). FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, log rank test). FGF-induced signalling is targeted using soluble FGF receptor (sFGFR), potent inhibitor of FGFR function. We have previously shown that sFGFR expression via a replication-deficient adenoviral vector (AdlllcRl) suppresses in vitro FGF-induced signalling and function in human CaP DU145 cells. We tested the significance of inhibiting FGF function along with conventional therapeutic modalities in CaP, and confirmed synergistic effects on in vitro cell growth (proliferation and colony formation) by combining sFGFR expression and treatment with either Paclitaxel (Taxol) or gamma-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP.
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PMID:Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer. 1565 58

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